The attached proposal describes a 5 year research plan designed to investigate responses in C.elegans to proteome damage resulting from cellular metabolism or specific exogenous toxins using genetics, transgenic animals, and RNAi. Damage to the proteome contributes to the harmful effects of environmental and occupational exposures, the pathogenesis of specific diseases including neurodegenerative diseases, cancer, and diabetes, and likely even the aging process itself. Sources of proteome damage include oxidative stress, unstable proteins, infections, and exogenous chemicals such as heavy metals and electrophilic organic compounds. We have recently found that several electrophilic tyrosine metabolites are a potent endogenous source of proteotoxic stress. Further, these metabolites also induce the expression of AIRAP/aip-1 which is a recently described family of proteins that are induced by arsenic exposure and serve to augment the clearance of damaged proteins via the proteosome. Our finding makes tyrosine degradation products the first identified endogenous activator of the aip-1 pathway. The AIRAP/aip-1 genes are also interesting in that they are induced by exposures, like arsenic or tyrosine metabolites, that produce oxidative, ER, and heat shock-like stresses to affected cells, but classic exposures, like heat, peroxide, or tunicamycin, that produce a more limited spectrum of damage fail to induce AIRAP/aip-1. Hence, the induction of AIRAP/aip-1 has a great deal of specificity which is currently not understood. We identified three transcription factors, skn-1, elt-2, and F57B10.1, as being required for the induction of aip-1 by tyrosine metabolites. Our proposal seeks to understand how the presence of AIRAP/aip-1 inducers is perceived, is communicated to these transcription factors, and leads to the activation of aip-1 and perhaps additional co-regulated stress response genes. The experiments involve using transgenic animals, a yeast one-hybrid screen, and RNAi to study how aip-1 is regulated;using genetics to find genes involved in identifying proteome damage and relaying this information to produce aip-1 expression;and using RNAi to see if other inducers, such arsenic, utilize similar pathways to induce aip-1 expression. PUBLIC HEALTH RELEVANCE: Our project aims to study how cells respond to damage from external toxins or cellular metabolism using the non-parasitic worm C. elegans. We hope to provide new insights into these responses which might lead to new treatments to prevent diseases like diabetes.